Inhibitor Report for: SM-10888

A U-shaped dialysis cannula was implanted into rat frontal cortex, hippocampus and striatum, and after 1 day for surgical recovery the cannula was perfused with Ringer's solution without any acetylcholinesterase (AChE) inhibitor under freely moving conditions. With a highly sensitive assay method for acetylcholine (ACh), the basal ACh content in the dialysates were detectable in those brain regions for several hours. The basal levels in the frontal cortex, hippocampus and striatum were 82 +/- 9, 72 +/- 4, 70 +/- 8 fmol/20 microliters (mean +/- S.E.M.), respectively. When SM-10888, a novel AChE inhibitor and putative therapeutic drug for Alzheimer's disease, was injected intraperitoneally, ACh in the dialysate of the cortex increased in a dose-dependent manner. Changes in the levels of hippocampal and striatal ACh release evoked by SM-10888 were similar to, but smaller than, that in the cortex. These data suggest that since the present assay method is able to determine in vivo basal ACh release in the dialysate without any AChE inhibitor, it is possible to study the effect of a novel drug such as SM-10888 in the brain regions.

The effects of the compound SM-10888 (9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate) in a number of pharmacological and biochemical tests were studied and compared to those of tacrine (THA), amiridin, HP-029 and physostigmine. SM-10888 inhibited cholinesterase activity (IC50: 2.3 x 10(-7) M) in rat cortical P2 fraction with almost the same potency as THA, while SM-10888 was 2-4 times more potent than amiridin and HP-029, but about 10 times less potent than physostigmine. When given to mice p.o., SM-10888 induced central (hypothermia) and peripheral (salivation) cholinergic effects. When the ratio of the ED50 value for hypothermia to that for salivation was regarded as the index of the selectivity to the central nervous system (CNS), SM-10888 was shown to be about 3 times more selective to the CNS than the other four drugs in mice. The minimum effective dose of SM-10888 for its increasing effect on acetylcholine (ACh) content in the mouse cerebral cortex was about 10 times higher than that of physostigmine, but 5-10 times lower than those of THA, amiridin and HP-029. These results suggest that SM-10888 is an adequate drug for increasing the brain ACh content with less peripheral cholinergic side effects than THA, amiridin, HP-029 and physostigmine.

The effects of the tacrine (THA) derivative SM-10888 (9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate) on habituation and passive avoidance responses were studied in mice. We examined its effects on habituation of exploratory activity, measured by photo-cell beam interruptions in a small, simple cage and cycloheximide (CXM)- or electroconvulsive shock (ECS)-induced stepdown type passive avoidance response (PAR) failures in comparison with those of THA, amiridin, HP-029 and physostigmine. SM-10888 (6 mg/kg, p.o.) administered post-acquisition session enhanced the retention of habituation. CXM- and ECS-induced PAR failures were improved by SM-10888 (6 mg/kg, p.o.) administered at pre-training or post-training, respectively. THA enhanced the retention of habituation and improved CXM-induced PAR failure at 30 mg/kg, p.o., but did not affect ECS-induced PAR failure at 1-15 mg/kg, p.o. Amiridin and HP-029 were also effective on habituation and CXM-induced PAR failure at 40-50 mg/kg, p.o., but did not affect ECS-induced PAR failure at the tested doses. Physostigmine showed a moderate improvement only in CXM-induced PAR failure. The results indicate that SM-10888 enhanced habituation and improved PAR failures at much lower doses than THA. This seems to depend on its high selectivity to the central nervous system.

To investigate how the physicochemical properties and pharmacokinetics of SM-10888 are altered by metabolic reactions, physicochemical and pharmacokinetic parameters of its phase I and phase II metabolites were determined. The metabolic pathways of SM-10888 in rats include oxidation at the C1 position (via the hydroxylated metabolite M3 to the cyclic ketone M4) and glucuronidation of both SM-10888 and M3 (SMG and M3G). Partition coefficients between n-octanol/pH 7.4 buffer (logP*) were determined to be 2.23 for SM-10888, 1.59 for M3, 2.66 for M4, -1.37 for SMG, and -1.72 for M3G. The phase I metabolite M3 showed lower lipophilicity and serum protein binding at pH 7.4, and larger renal clearance (CLr) than SM-10888. In contrast, the further oxidized metabolite M4 demonstrated higher lipophilicity and protein binding and lower CLr than SM-10888 and M3. Among these nonconjugated forms, only the pKa value of M4 was found to be below 7.4 (6.2 for M4, 8.5 for SM-10888, and 8.0 for M3), indicating that M4 exists in a more lipophilic nonionized form at the physiological pH, whereas SM-10888 and M3 are present as ionized forms. The significant shift in pKa of M4 could be the result of a cooperative effect of the electron withdrawing carbonyl group and resonating structure allowing hydrogen bond formation between CO and NH2 group, and might explain its high lipophilicity and low CLr. Glucuronidation significantly increased hydrophilicity with CLr's in excess of the glomerular filtration rate, suggesting involvement of active transport.

1. The metabolism of 9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate (SM-10888), a cholinesterase inhibitor was studied in rat. 2. The phase I metabolite (designated M3) was isolated from urine and identified as 1-hydroxylated SM-10888 by 1H-n.m.r. and EI-MS. 3. Two glucuronides (designated SMG and M3G) were isolated from bile and urine and their structures examined by FAB-MS/MS and beta-glucuronidase hydrolysis. 4. FAB-mass spectra of SMG and M3G showed molecular ions ([M+H]+) at m/z 405 and 421, respectively. In their daughter spectra, fragment ions of aglycones (SM-10888 and M3), generated by the loss of glucuronic acid (176 amu) were observed. The daughter spectra of these aglycones were essentially similar to those of the corresponding synthetic standards. 5. SMG was hydrolysed non-enzymically at pH 5 as is often the case with N-glucuronides of arylamines. M3G could be hydrolysed by beta-glucuronidase but proved stable at pH 5. 6. From these results, SMG and M3G were concluded to be the N-glucuronide of SM-10888 and the O-glucuronide of M3, respectively.

A U-shaped dialysis cannula was implanted into rat frontal cortex, hippocampus and striatum, and after 1 day for surgical recovery the cannula was perfused with Ringer's solution without any acetylcholinesterase (AChE) inhibitor under freely moving conditions. With a highly sensitive assay method for acetylcholine (ACh), the basal ACh content in the dialysates were detectable in those brain regions for several hours. The basal levels in the frontal cortex, hippocampus and striatum were 82 +/- 9, 72 +/- 4, 70 +/- 8 fmol/20 microliters (mean +/- S.E.M.), respectively. When SM-10888, a novel AChE inhibitor and putative therapeutic drug for Alzheimer's disease, was injected intraperitoneally, ACh in the dialysate of the cortex increased in a dose-dependent manner. Changes in the levels of hippocampal and striatal ACh release evoked by SM-10888 were similar to, but smaller than, that in the cortex. These data suggest that since the present assay method is able to determine in vivo basal ACh release in the dialysate without any AChE inhibitor, it is possible to study the effect of a novel drug such as SM-10888 in the brain regions.

The effects of the compound SM-10888 (9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate) in a number of pharmacological and biochemical tests were studied and compared to those of tacrine (THA), amiridin, HP-029 and physostigmine. SM-10888 inhibited cholinesterase activity (IC50: 2.3 x 10(-7) M) in rat cortical P2 fraction with almost the same potency as THA, while SM-10888 was 2-4 times more potent than amiridin and HP-029, but about 10 times less potent than physostigmine. When given to mice p.o., SM-10888 induced central (hypothermia) and peripheral (salivation) cholinergic effects. When the ratio of the ED50 value for hypothermia to that for salivation was regarded as the index of the selectivity to the central nervous system (CNS), SM-10888 was shown to be about 3 times more selective to the CNS than the other four drugs in mice. The minimum effective dose of SM-10888 for its increasing effect on acetylcholine (ACh) content in the mouse cerebral cortex was about 10 times higher than that of physostigmine, but 5-10 times lower than those of THA, amiridin and HP-029. These results suggest that SM-10888 is an adequate drug for increasing the brain ACh content with less peripheral cholinergic side effects than THA, amiridin, HP-029 and physostigmine.

The effects of the tacrine (THA) derivative SM-10888 (9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate) on habituation and passive avoidance responses were studied in mice. We examined its effects on habituation of exploratory activity, measured by photo-cell beam interruptions in a small, simple cage and cycloheximide (CXM)- or electroconvulsive shock (ECS)-induced stepdown type passive avoidance response (PAR) failures in comparison with those of THA, amiridin, HP-029 and physostigmine. SM-10888 (6 mg/kg, p.o.) administered post-acquisition session enhanced the retention of habituation. CXM- and ECS-induced PAR failures were improved by SM-10888 (6 mg/kg, p.o.) administered at pre-training or post-training, respectively. THA enhanced the retention of habituation and improved CXM-induced PAR failure at 30 mg/kg, p.o., but did not affect ECS-induced PAR failure at 1-15 mg/kg, p.o. Amiridin and HP-029 were also effective on habituation and CXM-induced PAR failure at 40-50 mg/kg, p.o., but did not affect ECS-induced PAR failure at the tested doses. Physostigmine showed a moderate improvement only in CXM-induced PAR failure. The results indicate that SM-10888 enhanced habituation and improved PAR failures at much lower doses than THA. This seems to depend on its high selectivity to the central nervous system.